US6284730B1 - Methods useful in the treatment of bone resorption diseases - Google Patents

Methods useful in the treatment of bone resorption diseases Download PDF

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US6284730B1
US6284730B1 US09/125,247 US12524798A US6284730B1 US 6284730 B1 US6284730 B1 US 6284730B1 US 12524798 A US12524798 A US 12524798A US 6284730 B1 US6284730 B1 US 6284730B1
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parathyroid hormone
bone
bone resorption
treatment
months
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John Dietrich
Sverker Ljunghall
Sven Sjögren
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Shire NPS Pharmaceuticals Inc
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NPS Allelix Corp Canada
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Priority to US10/389,797 priority patent/US7018982B2/en
Priority to US11/305,339 priority patent/US7507715B2/en
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Priority to US12/351,558 priority patent/US7749543B2/en
Priority to US12/822,089 priority patent/US8153588B2/en
Priority to US13/405,093 priority patent/US8765674B2/en
Assigned to DRUG ROYALTY L.P. 3 reassignment DRUG ROYALTY L.P. 3 SECURITY AGREEMENT Assignors: NPS PHARMACEUTICALS, INC.
Priority to US14/285,437 priority patent/US20140256632A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • the present invention relates to a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, for sequential use in the treatment of bone-related diseases.
  • bone is continuously subject to remodeling.
  • This is a process where bone resorption is closely linked to bone formation, through the concerted action of the bone active cells, i.e. the bone forming osteoblasts and the bone resorbing osteoclasts. These cells together form what is called a basal multicellular (metabolic) unit, or BMU.
  • the remodeling process starts with activation of the lining cells (the cells that cover the unmineralized bone).
  • the lining cells resorb the unmineralized bone, then retract and leave room for the osteoclasts which resorb the old, mineralized bone and create an environment which attracts the osteoblast to the same site.
  • the osteoblasts thereafter lay down the organic matrix, which subsequently is becoming mineralized to form new bone.
  • the resulting bone mass is thus determined by the balance between resorption by osteoclasts and formation by osteoblasts.
  • a high activation frequency increases the rate by which bone is being lost if there is a negative balance per remodeling cycle.
  • activation frequency is increased the space that is being occupied by remodeling, the remodeling space, is also increased. This will give a lowered bone mass, since a greater portion of the bone is subject to resorption as part of the remodeling process.
  • Osteoporosis is a disease which is characterized by a reduced amount of bone tissue, usually of normal composition, which has reduced strength due to a combination of low bone mass and impaired architecture, and therefore carries an increased risk of fractures.
  • osteoporosis is the result of negative bone balance per remodeling cycle, i.e. less bone is formed than is being resorbed.
  • a specific disease as responsible for the loss of bone (e.g. malabsorption of calcium and hypersecretion of corticosteroid hormones) but in the majority of patients no such disorder is identified.
  • Such patients are classified as having “primary” osteoporosis. Bone is lost with advancing age in both sexes, but in females there is generally an increased rate of loss during the first years after the menopause (hence the term “postmenopausal” osteoporosis).
  • a number of agents have been used for the prevention and treatment of bone loss and osteoporosis, e.g. estrogen, vitamin D and bisphosphonates, such as alendronate (for a review, see: Osteoporosis (Marcus, R., Feldman, D. and Kelsey, F., Eds.) Academic Press, San Diego, 1996).
  • Such agents mainly act through inhibition of bone resorption.
  • the antiresorptive agents can retard bone loss but, by definition, they do not increase bone mass within each remodeling unit. Many patients with fractures have severe bone loss at the time they come to clinical attention. Inhibition of bone resorption might not be enough to prevent fracture recurrences. Therefore it is urgent to develop therapies that can increase bone mass, i.e. anabolic agents.
  • Parathyroid hormone is an 84 amino acid polypeptide which is normally secreted from the parathyroid glands. PTH has an important physiological role to maintain serum calcium within a narrow range. Furthermore, it has anabolic properties when given intermittently. This has been well documented in a number of animal and open clinical studies, recently reviewed by Dempster, D. W. et al. (Endocrine Reviews 1993, vol. 14, 690-709). PFH has a multitude of effects on bone. Part of it is through the remodeling cycle. PTH causes both increased activation frequency and a positive balance per cycle.
  • Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Synthetic human PTH is commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in e.g. EP-B-0383751.
  • the activation frequency is doubled.
  • bone mass or bone density
  • bone mineral density is increased by 5 to 10% per year in the lumbar spine and is largely unaffected in the femoral neck, which contains a higher proportion of cortical bone.
  • the presently known methods for treatment of osteoporosis utilize bone resorption inhibition of the BMU cycle, but have the drawbacks that their onset of effect is slow and limited, and that they only cause moderate increases of bone mineral density (bone mass) and may therefore be insufficient for the treatment of patients with osteoporosis in a stage where there is high risk of recurrent fractures. Furthermore, it has not been shown that present methods can improve on the altered architecture that is a hallmark of advanced osteoporosis.
  • a method of treatment of bone metabolism disorders utilizing the order of events in the BMU cycle, and comprising administering a bone active phosphonate and, sequentially, parathyroid hormone, is disclosed in WO 96/07417 (The Procter & Gamble Company).
  • the bone active phosphonate is given for a period of greater than about 6 months, in various dosage regimens, but always prior to PTH.
  • Hodsman, A. et al. J. Bone and Mineral Research, Vol. 10, Suppl. 1, abstract No. P288, p. S200, 1995 discloses a clinical trial involving treatment with PTH for 28 days, with or without sequential calcitonin for 42 days, with this cycle repeated at 3 months intervals for 2 years. Patients were then crossed over to clodronate, 28 days per 3 months, for one year. However, there was no beneficial effect in bone density from this sequential PTH/bisphosphonate treatment regimen.
  • WO 97/31640 discloses a pharmaceutical composition comprising (a) an estrogen agonist/antagonist; and (b) a bone activating compound, such as parathyroid hormone.
  • a pharmaceutical composition comprising (a) an estrogen agonist/antagonist; and (b) a bone activating compound, such as parathyroid hormone.
  • the periods of treatment are broadly defined and it is stated that the said compounds can be administered for periods from about three months to about three years.
  • the anabolic agent when the anabolic agent was administered initially, ie. as the starting point, and is then followed by administration of the resorption inhibitor, the total increase in BMD is not only maintained but also much further increased. It appears that the initial increase in activation frequency by the anabolic agent creates not only formation of new bone, but also a large remodeling space. Subsequent administration by the resorption inhibitor, inhibits further increases in the remodeling space, by decreasing the activation frequency. Upon closing, or diminishing, the existing remodeling space, BMD is then allowed to increase more than was achieved during treatment with the anabolic agent alone during the first period.
  • the present invention is thus based on the concept of remodeling.
  • overriding the resorptive phase of the BMU over several consecutive cycles it fortifies the anabolic action of PTH.
  • prolonging the treatment over several BMU cycles it takes advantage of the opposite influences on the activation frequency which is increased by PTH and later reduced by bisphosphonates.
  • WO 96/07417 discloses a method of treatment of bone metabolism disorders, comprising administering a bone active phosphonate and, subsequently, parathyroid hormone.
  • the bone active phosphonate was thus given prior to PTH.
  • the order of treatment regimens provides principally different treatment responses. Slowing down the remodeling cycle with a resorption inhibitor would limit the maximum anabolic effect that can be obtained with PTH.
  • PTH is given first over several BMU cycles, not only will it enhance the BMU positive bone balance significantly, it will also increase activation frequency to such an extent that effects of subsequent antiresorptive therapy will be enhanced.
  • a bisphosphonate is given after PTH treatment, in order not only to maintain bone mass on the higher level by its antiresorptive action, but also to increase BMD by filling in the increased remodeling space through the reduction of activation frequency.
  • treatment with an agent that increases the activation frequency must be of sufficient duration, ie. it must cover several BMU cycles (e.g. 6 to 12 months). Only then can the full potential of the treatment, with regards to increases in BMD, develop.
  • the method of treatment according to the invention achieves the advantageous result that bone mass is first rapidly increased during PTH treatment and thereafter further bone mineral density is gained, compared to the results achieved with bisphosphonates alone without prior activation by PTH.
  • the present invention provides in a first aspect a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months, preferably about 12 (or above 12) months to 24 months or about 12 (or above 12) months to 18 months, or more preferably about 18 months; and (b) after the administration of said parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 6 to 36 months, preferably about 12 to 36 months or about 12 to 18 months, or more preferably about 12 months.
  • This sequence of treatments can be repeated at intervals of one to five years, until BMD has reached a value corresponding to “young normal mean”.
  • the interval between treatments coincides with the period of one treatment cycle, i.e. 12 to 60 months, preferably 24 to 60 months or 24 to 42 months, or more preferably 30 to 36 months.
  • PTH parathyroid hormone
  • thyroid hormone encompasses full-length PTH(1-84) as well as PTH fragments. It will thus be understood that fragments of PTH variants, in amounts giving equivalent biological activity to PTH(1-84), can be incorporated in the formulations according to the invention, if desired. Fragments of PTH incorporate at least the amino acid residues of PTH necessary for a biological activity similar to that of intact PTH. Examples of such fragments are PTH(1-31), PTH(1-34), PTH(1-36), PTH(1-37), PTH(1-38), PTH(1-41), PTH(28-48) and PTH(25-39).
  • thyroid hormone also encompasses variants and functional analogues of PTH.
  • the present invention thus includes pharmaceutical formulations comprising such PTH variants and functional analogues, carrying modifications like substitutions, deletions, insertions, inversions or cyclisations, but nevertheless having substantially the biological activities of parathyroid hormone.
  • Stability-enhanced variants of PTH are known in the art from e.g. WO 92/11286 and WO 93/20203.
  • Variants of PTH can e.g. incorporate amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18, and replacement of asparagine at position 16. Cyclized PTH analogues are disclosed in e.g. WO 98/05683.
  • the invention includes a preparation as described above wherein the said parathyroid hormone is selected from the group consisting of:
  • biologically active should be understood as eliciting a sufficient response in a bioassay for PTH activity, such as the rat osteosarcoma cell-based assay for PTH-stimulated adenylate cyclase production (see Rodan et al. (1983) J. Clin. Invest. 72, 1511; and Rabbani et al. (1988) Endocrinol. 123, 2709).
  • the PTH to be used in the pharmaceutical preparation according to the invention is preferably recombinant human PTH, such as full-length recombinant human PTH.
  • Parathyroid hormone can be subcutaneously administered in an amount of approximately 0.1 to 5 ⁇ g/kg body weight, preferably 0.5 to 3 ⁇ g/kg, or more preferably 1 to 2.5 ⁇ g/kg body weight.
  • nasally or pulmonary, PTH can be administered in an amount of 0.1 ⁇ g to 15 mg/kg.
  • the said bone resorption inhibitor can be a bisphosphonate, e.g. alendronate; or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g. raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, or levormeloxifene; or a calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
  • a bisphosphonate e.g. alendronate
  • a substance with estrogen-like effect e.g. estrogen
  • a selective estrogen receptor modulator e.g. raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, or levormeloxifene
  • a calcitonin-like substance e.g. calcitonin
  • the said bone resorption inhibitor is preferably administered in an amount of 0.05 to 500 mg, preferably around 10 mg.
  • the invention provides the use of parathyroid hormone in combination with a bone resorption inhibitor in the manufacture of a medicament for the treatment or prevention of bone-related diseases, in particular osteoporosis, said medicament being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months.
  • the parathyroid hormone and the bone resorption inhibitor are as defined above.
  • the invention provides a method of treatment or prevention of bone-related diseases, in particular osteoporosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical preparation as defined in the above. Consequently, such a method comprises administering to a mammal, including man, in need of such treatment (a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and (b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
  • the invention also includes a method of treatment or prevention of bone-related diseases which comprises administering, to a patient who has already been subject to treatment with parathyroid hormone during a period of approximately 6 to 24 months, after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.

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Abstract

The invention relates to a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months.

Description

This appln. is a 371 of PCT/SE98/01095, filed Jun. 8, 1998.
TECHNICAL FIELD
The present invention relates to a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, for sequential use in the treatment of bone-related diseases.
BACKGROUND ART
Bone Formation and Resorption
In the adult individual (males as well as females) bone is continuously subject to remodeling. This is a process where bone resorption is closely linked to bone formation, through the concerted action of the bone active cells, i.e. the bone forming osteoblasts and the bone resorbing osteoclasts. These cells together form what is called a basal multicellular (metabolic) unit, or BMU. The remodeling process starts with activation of the lining cells (the cells that cover the unmineralized bone). The lining cells resorb the unmineralized bone, then retract and leave room for the osteoclasts which resorb the old, mineralized bone and create an environment which attracts the osteoblast to the same site. The osteoblasts thereafter lay down the organic matrix, which subsequently is becoming mineralized to form new bone. The resulting bone mass is thus determined by the balance between resorption by osteoclasts and formation by osteoblasts.
Consequently, there is a close relationship between the actions of the two cell types which is referred to as “coupling”; bone resorption always precedes bone formation. The coupling phenomenon means that even when the intention is to produce a positive balance per cycle it is still necessary to start with bone resorption. Typically, a BMU cycle takes 3 to 6 months to complete.
The rate by which the basal metabolic (multicellular) units are being activated, the activation frequency, also plays a role. A high activation frequency increases the rate by which bone is being lost if there is a negative balance per remodeling cycle. When activation frequency is increased the space that is being occupied by remodeling, the remodeling space, is also increased. This will give a lowered bone mass, since a greater portion of the bone is subject to resorption as part of the remodeling process.
The above outlined sequence of events is well known in the art and has formed the basis for the understanding of metabolic bone diseases and possible ways for their treatments.
Osteoporosis is a disease which is characterized by a reduced amount of bone tissue, usually of normal composition, which has reduced strength due to a combination of low bone mass and impaired architecture, and therefore carries an increased risk of fractures. In terms of remodeling, osteoporosis is the result of negative bone balance per remodeling cycle, i.e. less bone is formed than is being resorbed. In a small proportion of patients it is possible to determine a specific disease as responsible for the loss of bone (e.g. malabsorption of calcium and hypersecretion of corticosteroid hormones) but in the majority of patients no such disorder is identified. Such patients are classified as having “primary” osteoporosis. Bone is lost with advancing age in both sexes, but in females there is generally an increased rate of loss during the first years after the menopause (hence the term “postmenopausal” osteoporosis).
Bone Resorption Inhibitors
A number of agents have been used for the prevention and treatment of bone loss and osteoporosis, e.g. estrogen, vitamin D and bisphosphonates, such as alendronate (for a review, see: Osteoporosis (Marcus, R., Feldman, D. and Kelsey, F., Eds.) Academic Press, San Diego, 1996). Such agents mainly act through inhibition of bone resorption. By reducing the resorbed amount in each remodeling cycle, while keeping the formation intact, it is possible to reduce the negative bone balance and retard bone loss. At the same time they reduce the activation frequency and since the remodeling space is reduced there is only a limited increase of bone mass.
Most studies with bisphosphonates indicate that they increase bone mineral density of the lumbar spine in the actively treated patients with around 1 to 5%, depending on dose and type of bisphosphonate, during the first year of treatment, when compared with control patients given placebo. Both patients and controls generally receive calcium supplementation to ensure adequate calcium nutrition.
The antiresorptive agents can retard bone loss but, by definition, they do not increase bone mass within each remodeling unit. Many patients with fractures have severe bone loss at the time they come to clinical attention. Inhibition of bone resorption might not be enough to prevent fracture recurrences. Therefore it is urgent to develop therapies that can increase bone mass, i.e. anabolic agents.
Parathyroid Hormone
Parathyroid hormone (PTH) is an 84 amino acid polypeptide which is normally secreted from the parathyroid glands. PTH has an important physiological role to maintain serum calcium within a narrow range. Furthermore, it has anabolic properties when given intermittently. This has been well documented in a number of animal and open clinical studies, recently reviewed by Dempster, D. W. et al. (Endocrine Reviews 1993, vol. 14, 690-709). PFH has a multitude of effects on bone. Part of it is through the remodeling cycle. PTH causes both increased activation frequency and a positive balance per cycle.
Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Synthetic human PTH is commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in e.g. EP-B-0383751.
PTH when given alone, to a patient with osteoporosis, will stimulate bone formation within each remodeling cycle and cause a positive bone balance within each cycle. At the same time the number of remodeling units will greatly increase, i.e. the activation frequency is enhanced. These two mechanisms act in different directions on bone mass.
During therapy with PTH it has been calculated that the activation frequency is doubled. Although this will mean that the remodeling space is increased, bone mass (or bone density) is increased in trabecular bone. Thus bone mineral density is increased by 5 to 10% per year in the lumbar spine and is largely unaffected in the femoral neck, which contains a higher proportion of cortical bone. These two sites are where the most common and clinically important fractures occur in the population, both in males and females.
The presently known methods for treatment of osteoporosis utilize bone resorption inhibition of the BMU cycle, but have the drawbacks that their onset of effect is slow and limited, and that they only cause moderate increases of bone mineral density (bone mass) and may therefore be insufficient for the treatment of patients with osteoporosis in a stage where there is high risk of recurrent fractures. Furthermore, it has not been shown that present methods can improve on the altered architecture that is a hallmark of advanced osteoporosis.
A method of treatment of bone metabolism disorders, utilizing the order of events in the BMU cycle, and comprising administering a bone active phosphonate and, sequentially, parathyroid hormone, is disclosed in WO 96/07417 (The Procter & Gamble Company). In that method, the bone active phosphonate is given for a period of greater than about 6 months, in various dosage regimens, but always prior to PTH.
Hodsman, A. et al. (J. Bone and Mineral Research, Vol. 10, Suppl. 1, abstract No. P288, p. S200, 1995) discloses a clinical trial involving treatment with PTH for 28 days, with or without sequential calcitonin for 42 days, with this cycle repeated at 3 months intervals for 2 years. Patients were then crossed over to clodronate, 28 days per 3 months, for one year. However, there was no beneficial effect in bone density from this sequential PTH/bisphosphonate treatment regimen.
WO 97/31640 (publication date Sep. 4, 1997) discloses a pharmaceutical composition comprising (a) an estrogen agonist/antagonist; and (b) a bone activating compound, such as parathyroid hormone. However, the periods of treatment are broadly defined and it is stated that the said compounds can be administered for periods from about three months to about three years.
DISCLOSURE OF THE INVENTION
Different combinations are conceivable for treating osteoporosis with resorption inhibitors and anabolic agents. The starting point for treatment, i.e. when the patient comes to the attention of the clinic, is a decreasing BMD (bone mineral density), due to the net formation rate being below the net resorption rate. Initial administration of a resorption inhibitor will reduce resorption rate by reducing the remodeling space and the activation frequency. Subsequent administration of an anabolic agent will then increase activation frequency and create an increased remodeling space. This coupling between resorption and reformation allows the formation rate to increase above the resorption rate and lead to increases in BMD. The resorption activity is a prerequisite for subsequent bone formation within the BMU.
However, it has surprisingly been found that when the anabolic agent was administered initially, ie. as the starting point, and is then followed by administration of the resorption inhibitor, the total increase in BMD is not only maintained but also much further increased. It appears that the initial increase in activation frequency by the anabolic agent creates not only formation of new bone, but also a large remodeling space. Subsequent administration by the resorption inhibitor, inhibits further increases in the remodeling space, by decreasing the activation frequency. Upon closing, or diminishing, the existing remodeling space, BMD is then allowed to increase more than was achieved during treatment with the anabolic agent alone during the first period.
The present invention is thus based on the concept of remodeling. By overriding the resorptive phase of the BMU over several consecutive cycles, it fortifies the anabolic action of PTH. In addition, by prolonging the treatment over several BMU cycles, it takes advantage of the opposite influences on the activation frequency which is increased by PTH and later reduced by bisphosphonates.
As mentioned above, WO 96/07417 discloses a method of treatment of bone metabolism disorders, comprising administering a bone active phosphonate and, subsequently, parathyroid hormone. The bone active phosphonate was thus given prior to PTH. The order of treatment regimens provides principally different treatment responses. Slowing down the remodeling cycle with a resorption inhibitor would limit the maximum anabolic effect that can be obtained with PTH. On the other hand, if PTH is given first over several BMU cycles, not only will it enhance the BMU positive bone balance significantly, it will also increase activation frequency to such an extent that effects of subsequent antiresorptive therapy will be enhanced.
According to the present invention, a bisphosphonate is given after PTH treatment, in order not only to maintain bone mass on the higher level by its antiresorptive action, but also to increase BMD by filling in the increased remodeling space through the reduction of activation frequency.
A BMU cycle, involving activation, resorption, formation, typically takes 3 to 6 months to complete. The number of BMU cycles acting concurrently determines the remodeling space. In order to create an increased and sustained remodeling space, treatment with an agent that increases the activation frequency must be of sufficient duration, ie. it must cover several BMU cycles (e.g. 6 to 12 months). Only then can the full potential of the treatment, with regards to increases in BMD, develop.
It has thus surprisingly been found that the method of treatment according to the invention achieves the advantageous result that bone mass is first rapidly increased during PTH treatment and thereafter further bone mineral density is gained, compared to the results achieved with bisphosphonates alone without prior activation by PTH. These findings are in contrast to previous studies in humans.
Consequently, the present invention provides in a first aspect a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months, preferably about 12 (or above 12) months to 24 months or about 12 (or above 12) months to 18 months, or more preferably about 18 months; and (b) after the administration of said parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 6 to 36 months, preferably about 12 to 36 months or about 12 to 18 months, or more preferably about 12 months.
This sequence of treatments can be repeated at intervals of one to five years, until BMD has reached a value corresponding to “young normal mean”. Preferably, the interval between treatments coincides with the period of one treatment cycle, i.e. 12 to 60 months, preferably 24 to 60 months or 24 to 42 months, or more preferably 30 to 36 months.
The term “parathyroid hormone” (PTH) encompasses naturally occurring human PTH, as well as synthetic or recombinant PTH (rPTH).
Further, the term “parathyroid hormone” encompasses full-length PTH(1-84) as well as PTH fragments. It will thus be understood that fragments of PTH variants, in amounts giving equivalent biological activity to PTH(1-84), can be incorporated in the formulations according to the invention, if desired. Fragments of PTH incorporate at least the amino acid residues of PTH necessary for a biological activity similar to that of intact PTH. Examples of such fragments are PTH(1-31), PTH(1-34), PTH(1-36), PTH(1-37), PTH(1-38), PTH(1-41), PTH(28-48) and PTH(25-39).
The term “parathyroid hormone” also encompasses variants and functional analogues of PTH. The present invention thus includes pharmaceutical formulations comprising such PTH variants and functional analogues, carrying modifications like substitutions, deletions, insertions, inversions or cyclisations, but nevertheless having substantially the biological activities of parathyroid hormone. Stability-enhanced variants of PTH are known in the art from e.g. WO 92/11286 and WO 93/20203. Variants of PTH can e.g. incorporate amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18, and replacement of asparagine at position 16. Cyclized PTH analogues are disclosed in e.g. WO 98/05683.
Consequently, the invention includes a preparation as described above wherein the said parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
(b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and
(d) biologically active variants of parathyroid hormone fragments.
In this context, the term “biologically active” should be understood as eliciting a sufficient response in a bioassay for PTH activity, such as the rat osteosarcoma cell-based assay for PTH-stimulated adenylate cyclase production (see Rodan et al. (1983) J. Clin. Invest. 72, 1511; and Rabbani et al. (1988) Endocrinol. 123, 2709).
The PTH to be used in the pharmaceutical preparation according to the invention is preferably recombinant human PTH, such as full-length recombinant human PTH. Parathyroid hormone can be subcutaneously administered in an amount of approximately 0.1 to 5 μg/kg body weight, preferably 0.5 to 3 μg/kg, or more preferably 1 to 2.5 μg/kg body weight. Orally, nasally or pulmonary, PTH can be administered in an amount of 0.1 μg to 15 mg/kg.
The said bone resorption inhibitor can be a bisphosphonate, e.g. alendronate; or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g. raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, or levormeloxifene; or a calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
The said bone resorption inhibitor is preferably administered in an amount of 0.05 to 500 mg, preferably around 10 mg.
In a further aspect, the invention provides the use of parathyroid hormone in combination with a bone resorption inhibitor in the manufacture of a medicament for the treatment or prevention of bone-related diseases, in particular osteoporosis, said medicament being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months. The parathyroid hormone and the bone resorption inhibitor are as defined above.
In yet a further aspect, the invention provides a method of treatment or prevention of bone-related diseases, in particular osteoporosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical preparation as defined in the above. Consequently, such a method comprises administering to a mammal, including man, in need of such treatment (a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and (b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
The invention also includes a method of treatment or prevention of bone-related diseases which comprises administering, to a patient who has already been subject to treatment with parathyroid hormone during a period of approximately 6 to 24 months, after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
EXAMPLE OF THE INVENTION
Postmenopausal females (n=172) with osteoporosis were given intact human PTH (1-84), as a subcutaneous injection, for one year in doses from 50 to 100 micrograms daily. It was shown that bone mineral density of the spine was increased in the lumbar spine, on the average by 8%. Increases in individual patients were considerably more than 10%. The changes of the femoral neck were smaller and ranged from 1 to 3%.
When administration of PTH was interrupted, some patients (approximately 60) were given the bisphosphonate alendronate in a standard dose of 10 mg for one year. After the combined treatment, bone mineral density was further increased in that group of patients. The average gain in the femoral neck over the two years was 6% and of the lumbar spine 15%. Again, some individual responses were considerably larger and amounted to more than 25% in the spine.
These new observations demonstrate that it is possible to achieve an enhanced effect on bone mineral density with the sequential administration of PTH and bisphosphonates.

Claims (29)

What is claimed is:
1. A method useful in the treatment of bone resorption diseases comprising administering to a mammal in need of such treatment or at increased risk to suffer from such disease:
(a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and
(b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 6 to 36 months.
2. The method according to claim 1, adapted for said administration of parathyroid hormone for approximately 12 to 24 months.
3. The method according to claim 2, adapted for said administration of parathyroid hormone for approximately 18 months.
4. The method according to any one of claims 1, 2, or 3, adapted for said administration of bone resorption inhibitor for approximately 12 to 36 months.
5. The method according to claim 4, adapted for said administration of bone resorption inhibitor for approximately 12 to 18 months.
6. The method according to claim 5, adapted for said administration of bone resorption inhibitor for approximately 12 months.
7. The method according to any one of claims 1, 2, or 3, wherein said parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
(b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and
(d) biologically active variants of parathyroid hormone fragments.
8. The method according to any one of claims 1, 2, or 3, wherein the bone resorption inhibitor is selected from the group consisting of a biphosphonate, a selective estrogen receptor modulator, calcitonin, a vitamin D analog, and a calcium salt.
9. The method according to any one of claims 1, 2, or 3 for the treatment of osteoporosis.
10. The method of claim 4, wherein the parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
(b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and
(d) biologically active variants of parathyroid hormone fragments.
11. The method of claim 5, wherein the parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
(b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and
(d) biologically active variants of parathyroid hormone fragments.
12. The method of claim 6, wherein the parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
(b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and
(d) biologically active variants of parathyroid hormone fragments.
13. The method of claim 4, wherein the bone resorption inhibitor is selected from the group consisting of a biphosphonate, estrogen, a selective estrogen receptor modulator, calcitonin, a vitamin D analog, and a calcium salt.
14. The method of claim 5, wherein the bone resorption inhibitor is selected from the group consisting of a biphosphonate, estrogen, a selective estrogen receptor modulator, calcitonin, a vitamin D analog, and a calcium salt.
15. The method of claim 6, wherein the bone resorption inhibitor is selected from the group consisting of a biphosphonate, estrogen, a selective estrogen receptor modulator, calcitonin, a vitamin D analog, and a calcium salt.
16. The method of any one of claims 1, 2, or 3, wherein the bone resorption inhibitor is selected from the group consisting of alendronate, estrogen, raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, levormeloxifene, and calcitonin.
17. The method of claim 4, wherein the bone resorption inhibitor is selected from the group consisting of alendronate, estrogen, raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, levormeloxifene, and calcitonin.
18. The method of claim 5, wherein the bone resorption inhibitor is selected from the group consisting of alendronate, estrogen, raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, levormeloxifene, and calcitonin.
19. The method of claim 6, wherein the bone resorption inhibitor is selected from the group consisting of alendronate, estrogen, raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, levormeloxifene, and calcitonin.
20. The method of claim 4 for the treatment of osteoporosis.
21. The method of claim 5 for the treatment of osteoporosis.
22. The method of claim 6 for the treatment of osteoporosis.
23. The method of claim 7 for the treatment of osteoporosis.
24. The method of claim 8 for the treatment of osteoporosis.
25. The method of any one of claims 1, 2, or 3, wherein the mammal is a human.
26. The method of claim 6, wherein the mammal is a human.
27. The method of claim 7, wherein the mammal is a human.
28. The method of claim 8, wherein the mammal is a human.
29. The method of claim 9, wherein the mammal is a human.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162716A1 (en) * 1997-06-19 2003-08-28 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US20040082937A1 (en) * 2002-09-04 2004-04-29 Dennis Ausiello Method and device for the controlled delivery of parathyroid hormone
US20050077584A1 (en) * 2001-06-28 2005-04-14 Uhland Scott A. Hermetically sealed microchip reservoir devices
US20050119183A1 (en) * 2003-11-12 2005-06-02 Nps Allelix Corp. Method for treating bone loss using parathyroid hormone
US20050182030A1 (en) * 2001-05-10 2005-08-18 American Pharmaceutical Partners, Inc. Liquid injectable formulation of disodium pamidronate
US20050234049A1 (en) * 2003-07-30 2005-10-20 Rajinder Singh Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
US20070001033A1 (en) * 2005-06-17 2007-01-04 Magneti Marelli Powertrain S.P.A. Fuel injector
US20070219132A1 (en) * 2005-11-10 2007-09-20 Board Of Control Of Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone
US7435814B2 (en) 2002-02-01 2008-10-14 Rigel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US7488316B2 (en) 2005-01-25 2009-02-10 Microchips, Inc. Control of drug release by transient modification of local microenvironments
US7576053B2 (en) 2005-06-13 2009-08-18 Rigel Pharmaceuticals, Inc. Methods and compositions for treating degenerative bone disorders
US20140249084A1 (en) * 2009-09-09 2014-09-04 Asahi Kasei Pharma Corporation Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units
US8987201B2 (en) 2009-12-07 2015-03-24 Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8052987B2 (en) 2000-06-20 2011-11-08 Novartis Pharmaceuticals Corporation Method of administering bisphosphonates
KR101320817B1 (en) 2001-06-01 2013-10-21 노파르티스 아게 Orally Administering Parathyroid Hormone and Calcitonin
WO2010115932A1 (en) * 2009-04-08 2010-10-14 Novartis Ag Combination for the treatment of bone loss
CA3056570C (en) 2011-12-13 2022-04-19 Amir Sagi Amorphous calcium carbonate for the treatment of calcium malabsorption and metabolic bone disorders
WO2016141250A1 (en) * 2015-03-03 2016-09-09 Radius Health, Inc. USES OF PTHrP ANALOGUE IN REDUCING FRACTURE RISK
IL256064B2 (en) 2015-06-04 2024-04-01 Amorphical Ltd Compositions of amorphous calcium carbonate for inhalation, sublingual or buccal administration
WO2018078616A1 (en) 2016-10-25 2018-05-03 Amorphical Ltd Amorphous calcium carbonate for treating a leukemia

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4698328A (en) 1985-04-04 1987-10-06 The General Hospital Corporation Method of increasing bone mass
US4822609A (en) * 1984-12-21 1989-04-18 The Procter & Gamble Company Treatment of osteoporosis
WO1989004173A1 (en) 1987-11-12 1989-05-18 Schering Corporation Acceleration of bone formation with gm-csf
US5118667A (en) * 1991-05-03 1992-06-02 Celtrix Pharmaceuticals, Inc. Bone growth factors and inhibitors of bone resorption for promoting bone formation
WO1992009304A1 (en) 1990-11-26 1992-06-11 Recker Robert R Treatment for osteoporosis using growth hormone release factor (grf) in combination with parathyroid hormone (pth)
WO1993011786A1 (en) 1991-12-17 1993-06-24 Procter & Gamble Pharmaceuticals, Inc. Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone
WO1996007417A1 (en) * 1994-09-09 1996-03-14 The Procter & Gamble Company Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone
WO1996007416A1 (en) 1994-09-09 1996-03-14 The Procter & Gamble Company Estrogens and parathyroid hormone for treating osteoporosis
US5510370A (en) 1993-07-22 1996-04-23 Eli Lilly And Company Parathyroid hormone and raloxifene for increasing bone mass
EP0792639A1 (en) * 1996-02-28 1997-09-03 Pfizer Inc. Combination therapy to treat osteoporosis or conditions which present low bone mass

Family Cites Families (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3768177A (en) 1972-08-02 1973-10-30 R Thomas Educational device
US3886132A (en) 1972-12-21 1975-05-27 Us Health Human parathyroid hormone
US4237224A (en) 1974-11-04 1980-12-02 Board Of Trustees Of The Leland Stanford Jr. University Process for producing biologically functional molecular chimeras
US4468464A (en) 1974-11-04 1984-08-28 The Board Of Trustees Of The Leland Stanford Junior University Biologically functional molecular chimeras
US4105602A (en) 1975-02-10 1978-08-08 Armour Pharmaceutical Company Synthesis of peptides with parathyroid hormone activity
US4016314A (en) 1975-06-26 1977-04-05 Hallco Inc. Embroidered fruit bowl wall hanging and kit for making same
US4264731A (en) 1977-05-27 1981-04-28 The Regents Of The University Of California DNA Joining method
US4366246A (en) 1977-11-08 1982-12-28 Genentech, Inc. Method for microbial polypeptide expression
US4199060A (en) 1978-07-20 1980-04-22 Howard Hardware Products, Inc. Lock installation kit
US4425437A (en) 1979-11-05 1984-01-10 Genentech, Inc. Microbial polypeptide expression vehicle
US4338397A (en) 1980-04-11 1982-07-06 President And Fellows Of Harvard College Mature protein synthesis
US4383066A (en) 1980-04-15 1983-05-10 Mitsubishi Gas Chemical Company, Inc. Polyphenylene ether resin composition
JPS5825439B2 (en) 1980-12-30 1983-05-27 株式会社林原生物化学研究所 Method for producing human parathyroid hormone
US4394443A (en) 1980-12-18 1983-07-19 Yale University Method for cloning genes
US4624926A (en) 1981-01-02 1986-11-25 The Research Foundation Of State University Of New York Novel cloning vehicles for polypeptide expression in microbial hosts
NO163060C (en) 1981-03-13 1990-03-28 Damon Biotech Inc PROCEDURE FOR THE PREPARATION OF SUBSTANCES MADE BY LIVING CELLS PRODUCING INTERFERONES OR ANTIBODIES.
US4385212A (en) 1981-10-05 1983-05-24 Bell Telephone Laboratories Incorporated Expandable communication terminal housing
US4424278A (en) 1981-11-16 1984-01-03 Research Corporation Cancer detection procedure using an acyl carrier protein
US4532207A (en) 1982-03-19 1985-07-30 G. D. Searle & Co. Process for the preparation of polypeptides utilizing a charged amino acid polymer and exopeptidase
US4546082A (en) 1982-06-17 1985-10-08 Regents Of The Univ. Of California E. coli/Saccharomyces cerevisiae plasmid cloning vector containing the alpha-factor gene for secretion and processing of hybrid proteins
US4595658A (en) 1982-09-13 1986-06-17 The Rockefeller University Method for facilitating externalization of proteins synthesized in bacteria
WO1984001173A1 (en) 1982-09-15 1984-03-29 Immuno Nuclear Corp Production of mature proteins in transformed yeast
DE3312928A1 (en) 1983-04-11 1984-11-22 Gesellschaft für Biotechnologische Forschung mbH (GBF), 3300 Braunschweig HUMAN PARATHORMON PRODUCING HYBRID VECTORS AND HUMAN PARATHORMONES
NZ207926A (en) 1983-04-25 1988-04-29 Genentech Inc Use of yeast #a#-factor to assist in expression of proteins heterologus to yeast
US4588684A (en) 1983-04-26 1986-05-13 Chiron Corporation a-Factor and its processing signals
US4637980A (en) 1983-08-09 1987-01-20 Smithkline Beckman Corporation Externalization of products of bacteria
CA1213537A (en) 1984-05-01 1986-11-04 Canadian Patents And Development Limited - Societe Canadienne Des Brevets Et D'exploitation Limitee Polypeptide expression method
ATE78515T1 (en) 1984-10-05 1992-08-15 Genentech Inc DNA, CELL CULTURES AND METHODS FOR HETEROLOGOUS PROTEIN SECRETION AND PERIPLASMIC PROTEIN RECOVERY.
JPS61267528A (en) 1984-11-26 1986-11-27 Yamanouchi Pharmaceut Co Ltd Transnasal calcitonin agent containing absorbefacient
IL95223A (en) 1984-12-06 1992-08-18 Synergen Biolog Inc Dna sequence for production of serine protease inhibitors
US4812311A (en) 1984-12-21 1989-03-14 The Procter & Gamble Company Kit for use in the treatment of osteoporosis
US4994559A (en) 1985-12-17 1991-02-19 Synergen, Inc. Human basic fibroblast growth factor
IE67035B1 (en) 1986-07-08 1996-02-21 Genetics Inst Production and use of non-glycosylated IL-6
US5010010A (en) 1986-10-22 1991-04-23 Selmer-Sande, A.S. Production of human parathyroid hormone from microorganisms
US5420242A (en) 1986-10-22 1995-05-30 Kaare M. Gautvik Production of human parathyroid hormone from microorganisms
AU8172787A (en) 1986-10-30 1988-05-25 Synergen Biologicals, Inc. Human pancreatic secretory trypsin inhibitors produced by recombinant dna methods and processes for the production of same
FI77278C (en) 1986-10-31 1989-02-10 Ahlstroem Oy Method and apparatus for combustion of soda black liquor.
US4833125A (en) 1986-12-05 1989-05-23 The General Hospital Corporation Method of increasing bone mass
FR2618914B1 (en) 1987-07-31 1991-12-06 Alain Souloumiac IMPROVEMENTS TO OPTOMAGNETIC SWITCHES
US5059587A (en) 1987-08-03 1991-10-22 Toyo Jozo Company, Ltd. Physiologically active peptide composition for nasal administration
US4904584A (en) 1987-12-23 1990-02-27 Genetics Institute, Inc. Site-specific homogeneous modification of polypeptides
US5223407A (en) 1988-08-31 1993-06-29 Allelix Inc. Excretion of heterologous proteins from e. coli
US5011678A (en) 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
USRE37919E1 (en) 1989-05-12 2002-12-03 The General Hospital Corporation Recombinant DNA method for production of parathyroid hormone
US5171670A (en) 1989-05-12 1992-12-15 The General Hospital Corporation Recombinant dna method for production of parathyroid hormone
US5744444A (en) * 1989-10-27 1998-04-28 Haemopep Pharma Gmbh HPTH-fragment-(1-37), the preparation thereof, medicaments containing same and the use thereof
DE3935738A1 (en) 1989-10-27 1991-05-08 Forssmann Wolf Georg DRUGS CONTAINING THE HUMAN PARATHORMONE FRAGMENT (1-37) AS AN ACTIVE AGENT
GB9020544D0 (en) 1990-09-20 1990-10-31 Sandoz Ltd Improvements in or relating to organic compounds
KR0131678B1 (en) 1991-12-09 1998-04-17 유미꾸라 레이이찌 Stabilized parathyroid hormone composition
IT1255723B (en) 1992-10-09 1995-11-13 USE OF PARATORMONE, ITS BIOLOGICALLY ACTIVE FRAGMENTS AND RELATED PEPTIDES, FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS USEFUL IN THE PREVENTION AND THERAPY OF ABORTION AND PRETERMONE BIRTH AND IN GENERAL FOR THE TREATMENT OF GESTATION
US5496801A (en) * 1993-12-23 1996-03-05 Allelix Biopharmaceuticals Inc. Parathyroid hormone formulation
US5747456A (en) * 1994-12-19 1998-05-05 Beth Israel Deaconess Medical Center Continuous low-dose administration of parathyroid hormone or its agonist
US5550134A (en) 1995-05-10 1996-08-27 Eli Lilly And Company Methods for inhibiting bone loss
US5599822A (en) 1995-06-06 1997-02-04 Eli Lilly And Company Methods for minimizing bone loss
HN1996000101A (en) * 1996-02-28 1997-06-26 Inc Pfizer COMBINED THERAPY FOR OSTEOPOROSIS
US5945412A (en) 1996-12-09 1999-08-31 Merck & Co., Inc. Methods and compositions for preventing and treating bone loss
SE9702401D0 (en) * 1997-06-19 1997-06-19 Astra Ab Pharmaceutical use

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822609A (en) * 1984-12-21 1989-04-18 The Procter & Gamble Company Treatment of osteoporosis
US4698328A (en) 1985-04-04 1987-10-06 The General Hospital Corporation Method of increasing bone mass
WO1989004173A1 (en) 1987-11-12 1989-05-18 Schering Corporation Acceleration of bone formation with gm-csf
WO1992009304A1 (en) 1990-11-26 1992-06-11 Recker Robert R Treatment for osteoporosis using growth hormone release factor (grf) in combination with parathyroid hormone (pth)
US5118667A (en) * 1991-05-03 1992-06-02 Celtrix Pharmaceuticals, Inc. Bone growth factors and inhibitors of bone resorption for promoting bone formation
WO1993011786A1 (en) 1991-12-17 1993-06-24 Procter & Gamble Pharmaceuticals, Inc. Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone
US5510370A (en) 1993-07-22 1996-04-23 Eli Lilly And Company Parathyroid hormone and raloxifene for increasing bone mass
WO1996007417A1 (en) * 1994-09-09 1996-03-14 The Procter & Gamble Company Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone
WO1996007416A1 (en) 1994-09-09 1996-03-14 The Procter & Gamble Company Estrogens and parathyroid hormone for treating osteoporosis
EP0792639A1 (en) * 1996-02-28 1997-09-03 Pfizer Inc. Combination therapy to treat osteoporosis or conditions which present low bone mass

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110071081A1 (en) * 1997-06-19 2011-03-24 Nps Pharmaceuticals, Inc. Methods useful in the treatment of bone resorption diseases
US7749543B2 (en) 1997-06-19 2010-07-06 Nps Pharmaceuticals, Inc. Methods useful in the treatment of bone resorption diseases
US8153588B2 (en) * 1997-06-19 2012-04-10 Nps Pharmaceuticals, Inc. Methods useful in the treatment of bone resorption diseases
US20090118192A1 (en) * 1997-06-19 2009-05-07 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US8765674B2 (en) 1997-06-19 2014-07-01 Nps Pharmaceuticals, Inc. Methods useful in the treatment of bone resorption diseases
US20030162716A1 (en) * 1997-06-19 2003-08-28 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US7018982B2 (en) * 1997-06-19 2006-03-28 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US20060211613A1 (en) * 1997-06-19 2006-09-21 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US7507715B2 (en) * 1997-06-19 2009-03-24 Nps Allelix Corp. Methods useful in the treatment of bone resorption diseases
US20050182030A1 (en) * 2001-05-10 2005-08-18 American Pharmaceutical Partners, Inc. Liquid injectable formulation of disodium pamidronate
US20050077584A1 (en) * 2001-06-28 2005-04-14 Uhland Scott A. Hermetically sealed microchip reservoir devices
US7497846B2 (en) 2001-06-28 2009-03-03 Microchips, Inc. Hermetically sealed microchip reservoir devices
US7655797B2 (en) 2002-02-01 2010-02-02 Rigel Pharmaceuticals, Inc. Intermediates for making 2,4-pyrimidinediamine compounds
US7435814B2 (en) 2002-02-01 2008-10-14 Rigel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US7557210B2 (en) 2002-02-01 2009-07-07 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7803939B2 (en) 2002-02-01 2010-09-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US8334296B2 (en) 2002-02-01 2012-12-18 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US8277440B2 (en) 2002-09-04 2012-10-02 Microchips, Inc. Implantable device for controlled, extended delivery of parathyroid hormone
US7497855B2 (en) 2002-09-04 2009-03-03 Microchips, Inc. Method and device for the controlled delivery of parathyroid hormone
US20040082937A1 (en) * 2002-09-04 2004-04-29 Dennis Ausiello Method and device for the controlled delivery of parathyroid hormone
US20090163895A1 (en) * 2002-09-04 2009-06-25 Microchips, Inc. Implantable device for controlled, extended delivery of parathyroid hormone
US20050234049A1 (en) * 2003-07-30 2005-10-20 Rajinder Singh Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
US7582648B2 (en) 2003-07-30 2009-09-01 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US8178671B2 (en) 2003-07-30 2012-05-15 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
US7452879B2 (en) 2003-07-30 2008-11-18 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US20050119183A1 (en) * 2003-11-12 2005-06-02 Nps Allelix Corp. Method for treating bone loss using parathyroid hormone
US7488316B2 (en) 2005-01-25 2009-02-10 Microchips, Inc. Control of drug release by transient modification of local microenvironments
US7576053B2 (en) 2005-06-13 2009-08-18 Rigel Pharmaceuticals, Inc. Methods and compositions for treating degenerative bone disorders
US20070001033A1 (en) * 2005-06-17 2007-01-04 Magneti Marelli Powertrain S.P.A. Fuel injector
US20070219132A1 (en) * 2005-11-10 2007-09-20 Board Of Control Of Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone
US7994129B2 (en) 2005-11-10 2011-08-09 Michigan Technological University Methods of using black bear parathyroid hormone
US20140249084A1 (en) * 2009-09-09 2014-09-04 Asahi Kasei Pharma Corporation Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units
US8987201B2 (en) 2009-12-07 2015-03-24 Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone

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